The present invention relates to intermediates for phosphonomethoxy nucleotide analogs, in particular intermediates suitable for use in the efficient oral delivery of such analogs.
Such analogs per se and various technologies for oral delivery of these and other therapeutic compounds are known. See WO 91/19721, WO 94/03476, WO 94/03466, WO 92/13869, U.S. Pat. No. 5,208,221, 5,124,051, DE 41 38 584 A1, WO 94/10539, WEJ7368583647920, WO 95 79/07919, WO 92/09611, WO 92/01698, WO 91/19721, WO 88/05438, EP 0 632 048, EP 0 481 214, EP 0 369 409, EP 0 269 947, U.S. Pat. Nos. 3,524,846 and 5,386,030, Engel, Chem. Rev. 77: 349-367 1997, Farquhar et al., J. Pharm. Sci. 72: 324-325 1983, Starrett et al., Antiviral Res. 19: 267-273 1992, Safadi et al., Pharmaceutical Research 10(9): 1350-1355 1993, Sakamoto et al., Chem. Pharm. Bull. 32(6): 2241-2248 1984, and Davidsen et al., J. Med. Chem. 37(26): 4423-4429 1994.
In accordance with this invention, compounds are provided having formula (1a) 
wherein Z is independently xe2x80x94OC(R2)2OC(O)X(R)a, an ester, an amidate or xe2x80x94H, but at least one Z is xe2x80x94OC(R2)2 OC(O)X(R)a;
A is the residue of an antiviral phosphonomethoxy nucleotide analog;
X is N or O;
R2 independently is xe2x80x94H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or xe2x80x94OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl;
R independently is xe2x80x94H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkyenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, xe2x80x94N(R4)2 or xe2x80x94OR3, where R4 independently is xe2x80x94H or C1-C8 alkyl, provided that at least one R is not H; and
a is 1 when X is 0 , or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be xe2x80x94OR3 or (c) both N-linked R groups can be xe2x80x94H;
and the salts, hydrates, tautomers and solvates thereof.
Further embodiments of the compounds of this invention are compounds of formula (1) 
wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl of their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
R is independently xe2x80x94H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or xe2x80x94OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl;
R1 is hydrogen, xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2F, xe2x80x94CHxe2x95x90CH2, or xe2x80x94CH2N3, or R1 and R8 are joined to form xe2x80x94CH2xe2x80x94;
R2 independently is hydrogen or C1-C6 alkyl; and
R8 is hydrogen or xe2x80x94CHR2xe2x80x94Oxe2x80x94C(O)xe2x80x94OR, or R8 is joined with R1 to form xe2x80x94CH2xe2x80x94;
and the salts, hydrates, tautomers and solvates thereof.
Other embodiments of this invention include a method for preparing a compound of formula (1a) which comprises reacting the diacid of a phosphonomethoxy nucleotide analog with LC(R2)2OC(O)X(R)a wherein L is a leaving group.
In particular embodiments of this invention, a method for preparing a compound of formula (1) is provided which comprises reacting a compound of formula (4) 
with LC(R2)2OC(O)X(R)a.
The abbreviations NMP, DMF and DMPU mean, respectively, N-methylpyrrolidinone, dimethylformamide and N,Nxe2x80x2-dimethylpropyleneurea.
Heterocycle means aromatic and nonaromatic ringed moieties. Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5- or 6-membered and typically contains 1 or 2 noncarbon atoms such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.
xe2x80x9cAlkylxe2x80x9d as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the form of normal, secondary, tertiary or cyclic structures. Examples are xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH(CH3) CH2CH3, xe2x80x94C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH (CH3)CH2CH2CH3, xe2x80x94CH(CH2CH3)2, xe2x80x94C(CH32CH2CH3, xe2x80x94CH(CH3)CH(CH3)2, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2CH (CH3)CH2CH3, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH(CH3) CH2CH2CH2CH3, xe2x80x94CH(CH2CH3)(CH2CH2CH3) xe2x80x94C(CH3)2CH2CH2CH3, xe2x80x94CH(CH3)CH(CH3)CH2CH3, xe2x80x94CH(CH3)CH2CH(CH3)2, xe2x80x94C(CH3)(CH2CH3)2, xe2x80x94CH (CH2CH3)(CH(CH3)2, xe2x80x94C(CH3)2CH(CH3)2, xe2x80x94CH(CH3C (CH3)3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl, 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.
xe2x80x9cAlkenylxe2x80x9d as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary or cyclic structures. Examples are xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94C(xe2x95x90CH2)(CH3), xe2x80x94CHxe2x95x90CHCH2CH3, xe2x80x94CH2CHxe2x95x90CHCH3, xe2x80x94CH2CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90C(CH3)2, xe2x80x94CH2C(xe2x95x90CH2) (CH3), xe2x80x94C(xe2x95x90CH2)CH2CH3, xe2x80x94C(CH3)2, xe2x80x94CH2C(xe2x95x90CH2) (CH3)CHxe2x95x90CH2, xe2x80x94Cxe2x95x90CHCH2CH2CH3, xe2x80x94CHCHxe2x95x90CHCH2CH3, xe2x80x94CHCH2CHxe2x95x90CHCH3, xe2x80x94CHCH2CH2CHxe2x95x90CH2, xe2x80x94C(xe2x95x90CH2)CH2CH2CH3, xe2x80x94C(CH3)xe2x95x90CH2CH2CH3, xe2x80x94CH(CH3)CHxe2x95x90CHCH3, xe2x80x94CH(CH3)CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90C(CH3)2, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
xe2x80x9cAlkynylxe2x80x9d as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary, or cyclic structures. Examples are xe2x80x94CCH, xe2x80x94CCCH3, xe2x80x94CH2CCH, xe2x80x94CCCH2CH3, xe2x80x94CH2CCCH3, xe2x80x94CH2CH2CCH, CH(CH3)CCH, xe2x80x94CCCH2CH2CH3, xe2x80x94CH2CCCH2CH3, xe2x80x94CH2CH2CCCH3 and xe2x80x94CH2CH2CH2CCH.
Salt(s) include those derived by combination of appropriate anions such as inorganic or organic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity. For example, one may form invention salts from acid addition of certain organic and inorganic acids, e.g., HF, CHl, HBr, HI, H2SO4, H3PO4, or from organic sulfonic acids, organic carboxylic acids to basic centers, typically a mines. Exemplary organic sulfonic acids include C6-C16 aryl sulfonic acids, C6-C16 heteroaryl sulfonic acids and C1-C16 alkyl sulfonic acids such as phenyl xcex1-naphthyl, xcex2-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acids include C1-C16 alkyl, C6-C16 aryl carboxylic acids and C4-C16 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids. Many amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically in one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used with synthetic intermediates of invention compounds. The salts of invention compounds may be crystalline or noncrystalline.
A is the residue of a phosphonomethoxy nucleotide analog. The parental compounds have the structure AOCH2P (O)(OH)2. They are well known and have demonstrated antiviral activity. Per se, they are not part of this invention. In general, A has the structure BQ wherein B is a purine or pyrimidine base or the aza and/or deaza analogs thereof and Q is a cyclic or acyclic aglycon. B is linked to Q through the purine 9 or pyrimidine 1 positions. Examples of these analogs can be found in U.S. Pat. Nos. 4,659,825, 4,724,233, 5,142,051 and 5,130,427, EP 369,409, EP 398,231, EP 494,370, EP 454,427, EP 270,885, EP 269,947, EP 452,935, WO 93/07157, WO 94/03567, and WO 96/23801. Typically, A will have the structure BCH2CH(CH3)xe2x80x94or BCH2CH2xe2x80x94.
The designation xe2x80x9caxe2x80x9d is an integer of 1 or 2. If X is N then a is 2 and one R is usually H and the other is not H. If X is O then a is 1.
B generally is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl. Ordinarily, B is adenin-9-yl or 2,6-diaminopurin-9-yl. In formula (1a) compounds, one Z optionally comprises an ester or an amidate. Suitable esters or amidates have been described, e.g., WO 95/07920. Exemplary esters are phenyl, benzyl, o-ethoxyphenyl, p-ethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-ethylmorpholino, C1-C8 O-alkyl and C1-C8 NH-alkyl. However, every compound of the invention will contain at least one xe2x80x94C(R2)2OC(O)X(R)a moiety.
R2 independently is xe2x80x94H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or xe2x80x94OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl. R2 is usually H or C1-C6 alkyl, and typically only one R2 is other than H. In most embodiments R2 is H in both instances. The carbon atom to which R2 is bonded is capable of chiral substitution, in which case R2 is in the (R), (S) or racemic configuration. In most, embodiments, if R2 is other than H the compounds of this invention are chirally enriched or pure at this site. In general, however, manufacturing is somewhat less expensive if chirality at the R2 carbon can be avoided. Thus, R2 is H when it is desired to help minimize the cost of synthesis.
X is O or N, typically O. The carbamates (where X=N) tend to be more stable in biological environments than the carbonates. When X is O then a is 1.
R independently is xe2x80x94H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkyenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, xe2x80x94N(R4)2 or xe2x80x94OR3, where R4 independently is xe2x80x94H or C1-C8 alkyl, provided that at least one R is not H. In general, R is C1-C6 secondary or normal alkyl which is unsubstituted or substituted with OR3. When X is N then a is 2. In the latter case one R is usually other than H. Alternatively, two N-linked R groups are joined to form a carbocycle or O-containing heterocycle, typically containing 3 to 5 carbon atoms in the ring. When R is unsaturated, but not aryl, the site of unsaturation is not critical and is in the Z or E configuration. The alkenyl chains of naturally occurring unsaturated fatty acids would be suitable as R groups, for example. R also includes cycloalkenyl or cycloalkynyl containing 1 or 2 unsaturated bonds, typically 1 unsaturated bond. When R is unsaturated, usually it is alkenyl or alkynyl without aryl substitution.
If R is substituted with halo, cyano, azido, nitro or OR3, typically R will contain 1 of these substituents. If substituted with 2 of these substituents, they are same or different. Generally, substituents found on R are OR3. An exemplary R group containing an OR3 substituent is xe2x80x94CH2C (CH2OCH3)(CH3)2.
When R contains an aryl group, the aryl group generally is bonded directly to X or is linked to X by methylene or ethylene. The aryl group may contain xe2x80x94Nxe2x95x90 or xe2x80x94Oxe2x80x94 as a ring atom. In general, the aryl group contains 5 or 6 carbons. If substituted, the aryl moiety is substituted with halo or OR3 in the ortho, meta or para positions, with R3 in this instance being typically C1-C3. Aryl groups containing 5 carbons are typically 2-, 3- or 4-pyridyl. In general, only one substituent group will be found on the aryl moiety if it is substituted at all. Exemplary aromatic and nonaromatic heterocyclic groups as used herein includes by way of example and not limitation the heterocycles described in Paquette, Leo A.; xe2x80x9cPrinciples of Modern Heterocyclic Chemistryxe2x80x9d (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; xe2x80x9cThe Chemistry of Heterocyclic Compounds, A series of Monographsxe2x80x9d (John Wiley and Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and xe2x80x9cJ. Am. Chem. Socxe2x80x9d, 82: 5566 (1960).
Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azoicyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3-H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, b-carbonlinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinolyl.
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 or a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or b-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
R includes the structure xe2x80x94C2-C6R5C2-C6 where each C2-C6 independently is a 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl moiety, e.g., ethylene, ethyl, propylene, propyl, isopropylene, isopropyl, cyclohexyl, etc., and R5 is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94 where R6 is linear, branched or cyclic alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
Embodiments include compounds where R4 is xe2x80x94H or xe2x80x94CH3.
R includes the structure xe2x80x94C2-C12R9, where each C2-C12 independently is a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon linear, branched or cyclic alkyl moiety, and R9 is 
N-piperidino, 2-pyridyl, 3-pyridyl or 4-pyridyl.
R also includes xe2x80x94C(CH2(X)0-1R7)3, xe2x80x94CH[C(CH2(X)o-1R7)3]2 and xe2x80x94CH2(C(X)o-1R7)3, where R7 is 1, 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl or R7 is 5 or 6 carbon aryl. In these embodiments, one or two X are typically present, usually 1, X is usually oxygen and R7 is typically methyl, ethyl, isopropyl, propyl or butyl, usually methyl.
R usually is phenyl, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, i-butyl, t-butyl, pentyl or 3-pentyl.
R1 is a substituent found in prior art phosphonomethoxy nucleotide analogs. R1 typically is any of hydrogen, xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2F, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2N3 or R1 and R8 are joined to form xe2x80x94CH2xe2x80x94. R1 is usually H or methyl. If R1 and R8 are joined to form methylene, B typically is cytosin-1-yl.
R3 is C1-C12 alkyl, but typically is C1-C6 alkyl.
Compounds of structure (1) typically are those in which B is adenin-9-yl, R1 is methyl or H, R8 is xe2x80x94CHR2xe2x80x94Oxe2x80x94C(O)xe2x80x94OR and R, R2 and R3 are set forth above.
The compounds of this invention are optionally enriched or resolved at the carbon atom chiral center linked to R1 in accordance with prior findings associating optimal antiviral activity with the configuration at this site. Thus, where R1 is methyl the compounds will be in (R) configuration at this center and will be substantially free of the (S) enantiomer.
Other embodiments include structure (10) and (11) compounds where R and each R2 are independently chosen and R2 is C1-C6 alkyl. 
Exemplary embodiments include the compounds named in Table B. Each compound in Table B is depicted as a compound having the formula (8) 
Compounds named in Table B are designated by numbers assigned to B, R, R1 and R2 according to the following convention, B.R.R1.R2 , using the numbered structures depicted in Table A. Thus, the compound named 1,2,3,4 specifies adenin-9-yl at B, xe2x80x94CH2CH3 at both R groups, xe2x80x94CH2OH at R1 and xe2x80x94(CH2)2CH3 at both R2 groups.
Exemplary embodiments include the following numbered groups of compounds.
1 Each compound named in Table B having only one carbonate moiety and a hydroxyl group linked to the phosphorus atom in place of the second carbonate moiety, i.e., Bxe2x80x94CH2xe2x80x94CHR1xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CHR2xe2x80x94O-C(O)xe2x80x94OR. Thus, the group 1 compound named 1.4.1.1 in Table B has the structure: adenin-9-yl-xe2x80x94CH2xe2x80x94CH (CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94OCH(CH3)2.
2 Compounds named in Table B having only one carbonate moiety and having only the R1 moiety, #3 (xe2x80x94CH2OH), which is modified such that R8 of formula (1) compounds is joined with R1 to form xe2x80x94CH2xe2x80x94. Thus, the group 2 compound named 1.4.3.1 in Table B has the structure: adenin-9-ylxe2x80x94CH2xe2x80x94CH(CH2xe2x80x94⋄)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(Oxe2x80x94⋄)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94OCH(CH3)2, where the symbols ⋄ indicate a covalent bond that links the oxygen and carbon atoms together.
3 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine base listed in Table A is the 3-deaza analog, e.g., 3-deazaadenin-9-yl. Thus, the group 3 compound defined in Table A and named 1.4.1.1 in Table B has the structure: 3-deazaadenin-9-ylxe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C (O)xe2x80x94OCH(CH3)2)2. The group 3 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure: 3-deazaadenin-9-ylxe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94OCH(CH3)2.
4 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine based listed in Table A is the 1-deaza analog, e.g., 1-deazaadenin-9-yl. Thus, the group 4 compound defined in Table A and named 1.4.1.1 in Table B has the structure: 1-deazaadenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C (O)xe2x80x94OCH(CH3(2)2. The group 3 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure:
5 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine based listed in Table A is the 8 -aza analog, e.g., 8-azaadenin-9-yl.
6 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
Thus, the group 6 compound defined in Table A and named 1.16.1.1 in Table B has the structure
adenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94cyclohexyl)2. The group 6 compound defined in Table A and named 1.16.1.1 in compound group 1 has the structure:
adenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94O-cyclohexyl. The group 6 compound defined in Table A and named 1.16.1.1 in compound group 3 has the structure.
7 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
8 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
9 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
10 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
11 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
12 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table a are replaced with the following groups:
13 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table a are replaced with the following groups:
14 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
15 The following groups of compounds A-J.
A Compounds named in groups 8-14 where the oxygen atom (xe2x80x94Oxe2x80x94) in the R moiety is replaced with xe2x80x94NHxe2x80x94.
B Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with xe2x80x94N(CH3)xe2x80x94.
C Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with xe2x80x94N(C2H5)xe2x80x94.
D Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with xe2x80x94N(CH2CH2CH3)xe2x80x94.
E Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with xe2x80x94N(CH(CH3)2xe2x80x94.
F Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with n-butyl substituted nitrogen (xe2x80x94N(CH2)3CH3)xe2x80x94).
G Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with i-butyl substituted nitrogen.
H Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with t-butyl substituted nitrogen.
I Compound named in groups 8-14 where the oxygen atom in the R moiety is replaced with linear, branched or cyclic 6 carbon alkyl substituted nitrogen.
Thus, the group 15B compound defined in Table A and named 1.1.1.1 in compound group 8 has the structure:
adenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)2N(CH3)2)2. The group 15B compound defined in Table A and named 1.1.1.1 in compound group 1, as named under group 8, has the structure:
adenin-9-yl-CH2-xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)2N(CH3)2.
The group 15B compound defined in Table a and named 1.16.1.1 in compound group 3, as named under group 8, has the structure:
3-deazaadenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94(CH2xe2x80x94P(O) (xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)2N(CH3)2)2.
16 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
In moieties 1-10, R9 is N-morpholino, in moieties 11-20, R9 is 2-pyridyl and in moieties 21-25, R9 is 3-pyridyl.
17 Compounds named in Table B and compounds named by compound groups 1-5 when R moieties 1-25 listed in Table a are replaced with the following groups:
In moieties 1-5, R9 is 4-pyridyl, in moieties 6-9 R9 is N-morpholino an din moieties 9-13, R9 is N-piperidyl.
18 The following groups of compounds A-J.
A Compounds named in Table B and compounds named by groups 1-17 where compound (8) is replaced with compound (9) 
where one R2 is as specified in Table A and the other R2 is xe2x80x94CH3.
B Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94CH2CH3.
C Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94(CH2)2CH3.
D Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94CH(CH2)2.
E Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94(CH2)3(CH3.
F Compounds named in Table b and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table a and the other R2 is xe2x80x94(CH2)4CH.
G Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94CH2CH(CH3)2.
H Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94C(CH3)3.
I Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94C5H11.
J Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is xe2x80x94C6H13.
Thus, the group 18A compound defined in Table A and named 1.4.2.3 in Table B has the structure:
adenin-9-yl-CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94P(O)(xe2x80x94Oxe2x80x94C (C2H5)(CH3)xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94CH(CH3)2)2. The group 18A compound defined in Table A and named 1.1.1.1 in compound group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CHxe2x80x942xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)2OCH3)2.
19 Compounds named in Table B and compounds named by compound groups 1-18 where compound (8) and compound (9) are replaced with compound (10) and (11) respectively 
where both R moieties are the same. Thus, the group 19 compound defined in Table A and named 1.4.1.1 in Table B has the structure:
adenin-9-yl-CH2xe2x80x94CH3xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Nxe2x80x94CH(CH3)2)2. The group 19 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure:
adenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94P(O)(OH)xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Nxe2x80x94CH(CH3)2. The group 19 compound defined in Table A and named 1.1.1.1 in compound group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CH2xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94CH2P(O)(xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94Nxe2x80x94(CH2)2OCH3)2.
The compounds of this invention are, to varying degrees, chemically stable. It is preferable that the compounds be chemically stable in order to ensure an adequate shelf-life and proper biodistribution upon oral administration. In general, embodiments are selected that have a t xc2xd at pH 7.4 of greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours and preferably in addition posses at t xc2xd at pH 2.0 of greater than 1, 10 or 100 hours. For example, the t-butyl carbonate found in Table 1 has a t xc2xd that is less stable than these parameters and therefor is not preferred. In addition, the optimal compounds of this invention should have bioavailability in beagle dogs (as set forth in more detail below) that exceeds about 20%, preferably, about 30%.
The carbamates and carbonates of this invention are prepared from the diacids of the phosphonomethoxy nucleotide analogs and the synthon LCH(R2)OC(O)X(R)a. L is a leaving group such as Cl, although it will be appreciated that any of the conventional leaving groups used in organic chemistry in nucleophilic substitution reactions can be successfully employed in place of chloro. In particular, leaving groups include halides, such as Cl, Br and I, and sulfonic acid esters such as methane, benzene or toluene sulfonic acid esters. The synthon is prepared by reacting LCH(R2)OC (O)L with HOR for preparation of the carbonate synthon or HNR2 for the preparation of the carbamate synthon. The synthon is then reacted with the nucleotide analog of choice, typically PMPA, to form the desired carbamate or carbonate adducts. The carbamates are prepared by reacting the synthon with the nucleotide analog under typical conditions of nucleophilic attack, for example in Et3N/DMF at room temperature. The carbonates are formed by reacting the appropriate synthon with the nucleotide analog in the presence of an organic base, typically an amine base. In addition, masked leaving groups such as thioesters, which may be activated by, for example, oxidation, and coupled directly to the phosphonic acid moiety may be used. Intermediates may be made with other leaving groups in this way, for example diphenylphosphinic acids, and others known in the chemistry of formacetals and glycosylation. 
Compounds where X=N and R=OR3 may be prepared by alkylation with the appropriate haloalkyl, O-alkyl carbamate. N,O-dialkylhydroxylamines are known in the literature, and may be prepared by alkylation of hydroxylamine, or by reductive amination of aldehydes or ketones with alkyl hydroxylamines. The dialkylhydroxylamines may be acylated with the appropriately substituted haloalkyl chloroformate under conditions analogous to those used to prepare the unsubstituted chloromethyl carbamates. Phosphonates may then be alkylated with the haloalkyl. O-alkyl carbamates to give the prodrugs under conditions used for the carbonates and carbamates. Leaving groups other than chloride may of course by used throughout.
In a typical method, the carbonate compounds of this invention are prepared by reacting Lxe2x80x94CHR2xe2x80x94Oxe2x80x94C(O)xe2x80x94OR with (4) to yield a compound of formula (1). 
The reaction typically proceeds in two concurrent steps in which the monoester forms first, and then the diester as the reaction proceeds longer. In this situation monoester is not typically isolated as an intermediate.
In order to make a diester than contains different carbonate or carbamate functionalities the monoester intermediate is recovered from the early reaction and the reaction is then completed with for example a second Lxe2x80x94CHR2xe2x80x94Oxe2x80x94C (O)xe2x80x94OR reagent, thereby resulting in substitution with a second ester different from the first.
One optionally conducts the carbonate synthesis reactions using at least about 1.0 and typically 2 equivalents of Lxe2x80x94CHR2xe2x80x94Oxe2x80x94C(O)xe2x80x94OR. The reaction is conducted in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100xc2x0 for about 4-72 hours. Exemplary suitable organic bases include triethylamine or Hunig base. Exemplary suitable organic solvents include DMF, DMPU, or NMP.
The monoester or diester products are purified by standard methods including flash column chromatography or salting out. Suitable salts for purification and/or formulation will final product include the sulfuric acid, phosphoric acid, lactic acid, fumaric or citric acid salts or complexes of the diester or monoester compounds of structures (1) or (1a).
The compounds of this invention are useful in the treatment or prophylaxis of one or more vital infections in man or animals, including infections caused by DNA viruses, RNA viruses, herpesviruses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, hepadnaviruses, (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV. Other infections to be treated with the compounds herein include MSV, RSV, SIV, FIV, MuLV, and other retroviral infections of rodents and other animals. The prior art describes the antiviral specificity of the nucleotide analogs, and the parental drug specificity is shared by the compounds of this invention. Dosages, viral targets, and suitable administration routes to best attack the site of infection are well known in the art for the parental drugs. Determination of proper doses is a straightforward matter for the clinician, taking into account the molecular weight of the compounds of this invention and, when administering them orally, their bioavailability in animals or as deduced in clinical trials with humans. Oral dosages of the compounds of this invention in humans for antiviral therapy will range about from 0.5 to 60 mg/Kg/day, usually about from 1 to 30 mg/Kg/day and typically about from 1.5 to 10 mg/Kg/day.
The compounds of this invention also are useful as intermediates in the preparation of detectable labels for oligonucleotide probes. The compounds are hydrolyzed to yield the diacid, diphosphorylated and incorporated into an oligonucleotide by conventional enzymatic or chemical means. The incorporated base from the compound of the invention will be capable of participating in base pairing and thus will not interfere substantially with the binding of the oligonucleotide to its complementary sequence (E. De Clercq Rev. Med. Virol. 3: 85-96 1993). However, if it does interfere with binding of the oligonucleotide containing the analog to the complementary sequence, the compound of the invention optionally is incorporated into the oligonucleotide as the 3xe2x80x2 terminal base, an innocuous position and a conventional site for oligonculeotide labeling. The aglycon donated by the nucleotide analog that is incorporated into the oligonucleotide is detected by any means, such as NMR or by binding to antibodies specific for the nucleotide analog.
Compounds of the invention and their pharmaceutically, i.e. physiologically, acceptable salts (hereafter collectively referred to as the active ingredients), are administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and dpidural). Generally, the compounds of this invention are administered orally, but if an embodiment is not sufficiently orally bioavailable it can be administered by any of the other routes noted above.
While it is possible for the active ingredients to be administered as pure compounds it is preferable to present them as pharmaceutical formulations. The formulations of the present invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The formulations include those suitable for topical or systemic administration, including oral, rectal, nasal, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient(s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. When formulated into an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane, 1,3-diol, mannnitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhances include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween(copyright) 60, Span(copyright) 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for a nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range of 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc). Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration are sterile and include aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof, of an active ingredient.
In addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administrating the composition to cats, dogs, horses, rabbits and other animals and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing a matrix or absorbent material and as active ingredient one or more compounds of the invention in which the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
All citations found herein are incorporated by reference.